Vitamin B12 deficiency is common in older adults, as well as in children and young adults in developing countries. Potential consequences of B12 deficiency include megaloblastic anemia and neurological degeneration, as well as increased risk of degenerative disorders such as vascular disease, cancer, and loss of cognitive function. The primary cause of B12 deficiency is malabsorption due to pernicious anemia and atrophic gastritis. In preliminary studies, circumstantial evidence has been obtained suggesting that a common polymorphism (G775C) in the B12 transport protein, transcobalamin II, affects B12 absorption and delivery to the tissues. Consequently, this polymorphism may influence an individual's susceptibility to B 12 deficiency caused by malabsorption. The primary goal of the present study is to directly assess the influence of the G775C polymorphism on B12 absorption and the kinetics of B12 metabolism. To accomplish this goal, a major technological advance available through collaboration with the Lawrence Livermore National Laboratories, called Accelerator Mass Spectrometry (AMS), will be employed. AMS provides the capacity to detect levels of carbon-14 (14C) in biological samples at attomolar concentrations. The technology is thus uniquely suited to detect the appearance of 14C in the blood, urine, and feces after oral ingestion of even small, minimally radioactive substrates. The specific aim of this proposal is to exploit AMS to assess the absorption and metabolism of 14C-labelled B12 in healthy human subjects who differ by which polymorphic variant of transcobalamin II they possess. The results of these studies will provide important basic information about the biological handling of B12 and may ultimately provide insight into the contribution of B12 deficiency to the risk of degenerative disease. Moreover, it is anticipated that the AMS technology will provide the means to develop a sensitive and specific method for assessment of B12 absorptive capacity in humans suspected of B 12 malabsorption. This novel method would ultimately replace the Schilling test, the current gold standard, but flawed and cumbersome method for clinical assessment of B 12 absorptive capacity.